Taiwanese Journal of Obstetrics & Gynecology 54 (2015) 316e318

Contents lists available at ScienceDirect

Taiwanese Journal of Obstetrics & Gynecology

journal homepage: www.tjog-online.com

Research Letter

Treatment options of endometriosis prior to in vitro fertilization/

intracytoplasmic sperm injection cycles to improve conception rate
Sudha Prasad a, *, Rupali Bassi a, Yogesh Kumar a, Ashok Kumar b, Saumya Prasad c
a

IVF & Reproductive Biology Centre, Department of Obstetrics and Gynecology, Maulana Azad Medical College, New Delhi, India
Department of Obstetrics and Gynecology, Maulana Azad Medical College, New Delhi, India
c
Department of Obstetrics and Gynecology, Vardhaman Mahavir Medical College, New Delhi, India
b

a r t i c l e i n f o
Article history:
Accepted 14 August 2014

Pain and infertility comprise a major part of the array of

symptoms among patients suffering from endometriosis. However,
the mechanism by which endometriosis acts as an etiological factor
of infertility is still to be deciphered.
Approach to a patient with severe forms of endometriosis varies
from laparoscopic cystectomy/ablation alone to cystectomy/ablation in conjunction with a long-acting gonadotropin-releasing
hormone analog.
To provide an update on contemporary treatment protocols, we
studied the patients undergoing in vitro fertilization (IVF) and
intracytoplasmic sperm injection (ICSI) in various stages of endometriosis. Various outcomes were studied in patients with
endometriosis-related infertility undergoing IVF by the long or
extended downregulated protocol, to achieve an outcome for
contradictory management of endometriosis-related infertility and
maximize conception in these patients.
This retrospective study was conducted at IVF & Reproductive
Biology Centre, Department of Obstetrics and Gynecology, Maulana
Azad Medical College and associated Lok Nayak Hospital, New
Delhi, India. Women (n 413; mean age standard deviation:
31.6 4.8 years) went through IVF/ICSI cycles between March 2008
and December 2012. Out of these, 34 (8.6%) patients diagnosed
with endometriosis and 161 (38.9%) with tubal factor infertility,
conrmed by laparoscopic chromopertubation, were enrolled for
IVF subsequently. We diagnosed endometriosis by visualization of
implants and/or cysts on laparoscopy and further conrmed it by a
histopathological biopsy. Endometriosis in these patients had also

* Corresponding author. Dr. Sudha Prasad, IVF & Reproductive Biology Centre,
Maulana Azad Medical College, 2-Bahadur Shah Jafar Marg, New Delhi 110002,
India.
E-mail address: drsprasad@yahoo.com (S. Prasad).

been surgically staged according to the Revised American Fertility

Society Classication [1]. Later, we performed cystectomy, adhesiolysis, and cauterization of the implants wherever possible. Three
patients of Stage IV had very poor ovarian reserve post endometriotic cystectomy/ablation, and were excluded from the study
and counseled to participate in the oocyte donor program. Out of
these conrmed 31 endometriotic patients, eight were of Stage I
endometriosis, two belonged to Stage II, six to Stage III, and 15 to
Stage IV. These patients were subjected to pituitary suppression
with GnRH agonist (GnRH-a) protocol for the IVF program. Stage I
patients were downregulated with short-acting leuprolide,
whereas those with Stage II had a single dose of long-acting GnRHa in depot form. Patients with Stages III and IV received three doses
of GnRH-a depot.
In Stage I, the short-acting GnRH-a leuprolide acetate 1.0 mg/
day (inj. Luperide; Sun Pharmaceutical Ind. Ltd., Halol, Baroda,
Gujrat, India) was administered in the midluteal phase of the previous cycle. In case of Patients with Stage II endometriosis, a single
injection of Goserelin acetate 3.6 mg in depot form (Zoladex; Astra
Zeneca, Luxembourg) was administered subcutaneously after
laparoscopic treatment, whereas Stage III and IV patients received
three injections of Goserelin acetate 3.6 mg subcutaneously every
28 days.
To compare the endometriotic group, we enrolled 31 odd agematched patients of tubal factors as controls by using a computergenerated list. After pituitary desensitization (E2 level < 50 pg/mL),
recombinant follicle-stimulating hormone (FSH) and/or human
menopausal gonadotropin (recombinant human FSH, inj. Folligraf;
and human menopausal gonadotropin, inj. Humog; Bharat Serums
and Vaccines Ltd, Ambernath, Mumbai, India) was used at doses
ranging between 225 IU/d and 450 IU/d, in accordance with body
mass index, patient age, size and number of follicles, and E2 levels.
These doses were modied according to folliculometry and serum
estradiol concentration. Human chorionic gonadotropin (10,000 IU,
Fertigyn; Sun Pharmaceutical Ind. Ltd., Halol, Baroda, Gujrat, India)
was administered intramuscularly when at least two follicles
reached a mean diameter of 18 mm. Oocyte retrieval was performed 34e35 hours after human chorionic gonadotropin injection
under transvaginal ultrasound. ICSI was performed in cases of poor

http://dx.doi.org/10.1016/j.tjog.2014.08.005
1028-4559/Copyright 2015, Taiwan Association of Obstetrics & Gynecology. Published by Elsevier Taiwan LLC. All rights reserved.

S. Prasad et al. / Taiwanese Journal of Obstetrics & Gynecology 54 (2015) 316e318

sperm quality at the time of oocyte retrieval, or low or no fertilization in previous cycles. Fertilization rate was dened as the ratio
of zygotes with two pronuclei observed 18e22 hours after insemination to the number of oocytes inseminated. Embryos were
scored using a classication system comprising cleavage stage,
variation of blastomere size, shape, fragmentation, and also multinucleation. Embryos were classied into four classes, from class 1
(high quality) to class 4 (low quality); class 4 embryos were not
transferred. After 3e5 days of oocyte retrieval, a maximum of two
to three high-quality embryos were transferred under ultrasound
guidance. Luteal support was provided in all patients with progesterone (50 mg, intramuscularly) in oil on alternate days and
micronized progesterone vaginal capsules 800 mg (Cap. Susten;
Sun Pharmaceutical Ind. Ltd., Halol, Baroda, Gujrat, India) daily in
two divided doses for the next 14 days after embryo transfer procedure. For conrmation of pregnancy, a urine pregnancy test was
conducted and serum beta human chorionic gonadotropin levels
were estimated on the 14th day.
Patient characteristics and ovarian stimulation parameters are
shown in Table 1. Women in the two groups (endometriosis-related
infertility and tubal factor groups) were comparable in terms of age,
body mass index, Day 3 FSH level, Day 3 antral follicle count, and
the FSH to luteinizing hormone (LH) ratio.
It was observed that the patients in the tubal factor group used a
lesser amount of gonadotropins, but duration of the stimulation was
comparable. This group further attained higher peak E2 (estradiol)
and P4 (progesterone) levels than women with endometriosis.
However, the progesterone to estradiol ratio was higher in the
endometriosis group than in the tubal group. The endometrial
thickness on the day of trigger, and the number of follicles > 15 mm
in size and their subsequent fertilization percentage as depicted by
the two pronuclear stages were signicantly higher in women with
tubal factor as compared to those with endometriosis. However,
even though the pregnancy rate in both groups was almost the
same. The pregnancy rate in the tubal factor group was 32.2% (10/
31) as compared to 29.8% (9/31) in the endometriotic group.
The main ndings of our study was that women with Stage I
endometriosis and those with Stages IIeIV post GnRH-a depot
administration had comparable pregnancy rates in fresh embryo
Table 1
Comparison between endometriosis-related infertility and tubal factor groups.
Parameters

Endometriosis
(mean SD)

Tubal
(mean SD)

No. of patients
Age
Duration of infertility
BMI
Recombinant
gonadotropins (IU)
hMG (IU)
Days of stimulation
Day 3 AFC
FSH
FSH to LH ratio
Total no. of oocytes
E2 levels on the day of
trigger
P4 levels on the day of
trigger
P4 to E2 ratio
ET (on trigger day)
Fertilization rate
Fertilization percentage
Clinical pregnancy (%)

31
30.44 0.663
6.19 3.820
24.63 3.213
1796.09 184.71

31
30.10 0.543
6.63 2.48
23.85 3.081
1563.71 188.04

0.171
0.483
0.986
0.425

183.02 157.15
9.28 3.185
8.75 0.774
6.23 2.081
1.92 1.493
7.59 4.8
1810.46 1688.84

1447 234.62
10.9 0.312
8.10 0.515
6.234 2.0810
1.83 1.73
11.23 8.31
2078.44 1605.18

0.03
0.023
0.049
0.489
0.423
0.022
0.957

1.07 1.122

1.39 1.39

0.206

4.09 5.023
9.44
50.9 0.620
66.71 2.37
25.8

1.87 5.33
10.14
78.7 0.920
80.84 6.83
29.03

0.068
0.008
0.105
0.009
0.289

AFC antral follicle count; BMI body mass index; ET endometrial thickness;
FSH follicle-stimulating hormone; hMG human menopausal gonadotropin;
LH luteinizing hormone; SD standard deviation.

317

transfer during the IVF/ICSI cycles to women with tubal factor

infertility, even after adjusting for confounding factors (25.8% in the
endometriosis group vs. 29.03% in the tubal group). The fertilization
rate was signicantly lower in the endometriosis group than that in
the tubal infertility group.
A meta-analysis of 22 published studies by Barnhart et al [2]
concluded that endometriosis interferes with all aspects of the
reproductive process, and therefore the pregnancy rate was much
lower than the tubal factor infertility. However, our ndings were
contradictory to the reports in the past and even to the recommendations by the European Society of Human Reproduction and
Embryology on IVF treatment in endometriosis.
According to the Society for Assisted Reproductive Technology
2004e2008, a study was conducted on > 23,000 assisted reproductive technique cycles with fresh endometrial thickness in
infertile women with endometriosis, which was compared with all
other indications for IVF. A total of ~450,000 cycles showed that in
all age strata, implantation and live birth rates were similar in
women with endometriosis compared to those in couples with
other infertility causes [3].
Despite severe degrees of an associated endometriosis, both the
tubal and the endometriosis groups had similar baseline FSH levels
and antral follicle counts (Table 1). This was in concurrence with
other studies [4].
The fertilization rate in the endometriosis group was signicantly lower as compared to the tubal factor group. In contrast to
our ndings, in a retrospective study in 2007 by Wu et al [4], a
signicantly lower total number of oocytes and mature oocytes
were retrieved, and no signicant difference in the fertilization rate
between the endometriosis and the tubal factor groups was seen.
Measurement of serum progesterone and estrogen in the midluteal phase has been tried to calculate the ratio between E2 and P4
hormones as a marker for endometrial receptivity, to subsequently
predict the occurrence of successful clinical pregnancies in IVF
cycles. Tajima et al [5] found that midluteal P4/E2 ratios were
signicantly different between conception cycles and nonconception cycles. However, the results of other studies were
contradicting [6,7]. The P4/E2 ratio observed in the endometriotic
group was higher than that in the tubal factor group in our study.
Endometriosis did not adversely affect pregnancy and live birth
rates, which is in line with the observations from large databases
such as SART [8].
Luteal phase downregulation with GnRH-a treatment is shown
to be superior to non-GnRH analog regimens in endometriosis
[9,10]. Surgical management of Stages III and IV of endometriosis
has been shown to have a detrimental effect on the ovarian reserve
and IVF outcomes [4].
Therefore, there is a need for a well-determined, less invasive
form of treatment that does not hamper the ovarian reserve and
improves IVF pregnancy rate. With judicious patient management,
the rate of clinical pregnancy in the endometriotic-related infertility patients can be equated to tubal factor infertility. Patients with
Stages II, III, and IV endometriosis should be administered with one,
two, and three doses of GnRH-a depot, respectively, after laparoscopic management to improve the outcome of IVF.
Conicts of interest
The authors have no conicts of interest relevant to this article.
References
[1] American Society for Reproductive Medicine. Revised American Society for
Reproductive Medicine classication of endometriosis: 1996. Fertil Steril
1997;67:817e21.

318

S. Prasad et al. / Taiwanese Journal of Obstetrics & Gynecology 54 (2015) 316e318

[2] Barnhart K, Dunsmoor-Su R, Coutifaris C. Effect of endometriosis on in vitro

fertilization. Fertil Steril 2002;77:1148e55.
[3] Society for Assisted Reproductive Technology. National Data Summary. 2008.
Available at: www.sartcorsonline.com/rptCSR PublicMult Year [accessed
November 2008].
[4] Wu MY, Chen SU, Chao KH, Chen CD, Yang YS, Ho HN. Mouse embryo toxicity
of IL-6 in peritoneal uids from women with or without endometriosis. Acta
Obstet Gynecol Scand 2001;80:7e11.
[5] Tajima C, Kawano T, Iwamasa J, Honda Y, Okamura H, Miyakita T, et al.
Midluteal progesterone/estradiol ratio as an indicator of pregnancy potential.
Nihon Naibunpi Gakkai Zasshi 1989;65:1278e85.
[6] Souter I, Hill D, Surrey MW. Midluteal estradiol-to-progesterone ratio (E2/P4)
has no effect on IVF outcome. Fertil Steril 2003;79:23e23.

[7] Abuelghar WM, Elsaeed MM, Tamara TF, Ellaithy MI, Ali MS. Measurement of
serum estradiol/progesterone ratio on the day of embryo transfer to predict
clinical pregnancies in intracytoplasmic sperm injection (ICSI) cycles. Is this of
real clinical value? Middle East Fertil Soc J 2013;18:31e7.
[8] Chedid S, Camus M, Smitz J, Van Steirteghem AC, Devroey P. Comparison
among different ovarian stimulation regimens for assisted procreation procedures in patients with endometriosis. Hum Reprod 1995;10:2406e11.
[9] Gomez-Torres MJ, Acien P, Campos A, Velasco I. Embryotoxicity of peritoneal
uid in women with endometriosis. Its relation with cytokines and lymphocyte populations. Hum Reprod 2002;17:777e81.
[10] Wunder DM, Mueller MD, Birkhauser MH, Bersinger NA. Increased ENA-78 in
the follicular uid of patients with endometriosis. Acta Obstet Gynecol Scand
2006;85:336e42.